Method for treating psoriasis

Description

24 Use of an effective amount of brilaroxazine or a pharmaceutically acceptable salt thereof. FIELD OF THE INVENTION

[001] The present invention relates to methods for treating psoriasis, comprising administering to an individual in need an effective amount of brilaroxazine, or a pharmaceutically acceptable salt thereof. FUNDAMENTALS

[002] Psoriasis is a systemic immune-mediated inflammatory disease with genetic components, distinguished by recurrent episodes of hyperkeratotic and erythematous plaques on the skin (Kamiya 2019, Aleem 2018). With a global prevalence of approximately 125 million, this condition manifests as phenotypically distinct subtypes, with plaque psoriasis representing more than 80% (Armstrong 2020, Raharja 2021). It significantly impairs the psychosocial functioning of patients, reducing their quality of life and, in extreme cases, causing depression, anxiety, or even suicidal ideation (Marek-Josefowicz 2022). In patients with mental illness, there appears to be a higher prevalence.

[003] Pathologically, psoriasis triggers the cutaneous inflammatory response through extrinsic (e.g., environmental, physical, and lifestyle) and intrinsic (e.g., mental and cardiometabolic) risk factors (Kamiya 2019). These stressors drive the activation of innate immune cells (e.g., dendritic cells) and the differentiation of adaptive immune cells (e.g., T cells into Th1 cells), which subsequently release pro-inflammatory cytokines (Cantrell 2018). These cytokines (e.g., tumor necrosis factor [TNF]-α, interferon-γ, and interleukins) lead to subsequent abnormal proliferation, dysfunctional differentiation, and leukocyte infiltration into lesional keratinocytes (Armstrong 2020). Systemic circulation of cytokines increases the risk of psoriatic arthritis, cardiometabolic diseases, and physiological conditions. Petition 870250088286, dated 09 / 29 / 2025, pp. 43 / 77 / 24 (Tashiro 2022, Wu 2022, Amin 2020).

[004] Psoriasis is a long-lasting, non-contagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity, from small localized areas to full body coverage.

[005] The five main types of psoriasis are plaque, guttate, inverse, pustular, and erythrodermic. Plaque psoriasis, also known as psoriasis vulgaris, accounts for about 90% of cases. It usually presents as red patches with overlying white scales. The most commonly affected areas of the body are the back of the forearms, shins, navel area, and scalp. Guttate psoriasis presents with drop-shaped lesions. Pustular psoriasis presents with small, non-infectious blisters filled with pus. Inverse psoriasis forms red patches in skin folds. Erythrodermic psoriasis occurs when the rash becomes very widespread and can develop from any of the other types. Fingernails and toenails are affected in most people with psoriasis at some point. This may include pitting or changes in nail color.

[006] Psoriasis is generally considered a genetic disease triggered by environmental factors. Symptoms often worsen during the winter and with certain medications, such as beta-blockers or nonsteroidal anti-inflammatory drugs (NSAIDs). Infections and psychological stress can also contribute. The underlying mechanism involves the immune system reacting to skin cells. Diagnosis is typically based on signs and symptoms.

[007] Psoriasis is a chronic-residual autoimmune inflammatory skin disease characterized by hyperproliferation of keratinocytes with erythematous plaques, hyperkeratosis, and silvery scales. Petition 870250088286, dated 09 / 29 / 2025, page 44 / 77 / 24 symmetrical distribution of predilection areas in the extensor region, scalp, and lumbosacral region. The exact cause is unknown, but there are several predisposing factors, such as genetics, environmental factors, trauma, infection, drugs, and psychological stress. It causes red, itchy, and scaly patches, most commonly on the knees, elbows, trunk, and scalp.

[008] The signs and symptoms of psoriasis can vary from person to person. Common signs and symptoms include: • Red patches of skin covered with thick, silvery scales • Small, scaly patches (commonly seen in children) • Dry, cracked skin that may bleed or itch • Itching, burning, or pain • Thickened nails with pits or ridges • Swollen and stiff joints

[009] Very rapid multiplication of keratinocytes occurs in people with psoriasis, and their displacement from the stratum basale (basal layer) to the upper layer of the epidermis occurs within 4 days. Thick, dry patches or plaques form, as the skin does not eliminate the cells quickly. Very mild psoriasis exists in some people, which may not even be suspected as a skin disorder. Very severe psoriasis can be observed in others, sometimes covering the entire body with thick, red, and scaly skin. Although psoriasis occurs in a population of all age groups, from pediatric to geriatric, it is usually diagnosed during adolescence. Other causal factors for psoriasis are genetics, sudden changes in genes (mutations), climate, immune system abnormalities, mental or emotional stress, contagion, and injuries. Petition 870250088286, dated 09 / 29 / 2025, page 45 / 77 / 24

[0010] Current treatments for psoriasis include topical therapy, phototherapy, and systemic therapy, the latter being reserved for severe cases. Topical corticosteroids and vitamin D derivatives remain first-line treatments, both as monotherapy and as an adjunct to systemic therapy, despite the disadvantages of limited systemic efficacy and long-term adverse effects (e.g., tachyphylaxis, skin atrophy, adrenal suppression, and skin irritation). Topical treatments can act rapidly and exert localized effects with minimal short-term adverse events. Conventional non-biological oral agents (e.g., methotrexate, apremilast, acitretin, or cyclosporine) offer more options for treating widespread inflammation; however, they are associated with significant toxicities (e.g., hepatotoxicity, nephrotoxicity, hypertension, dyslipidemia, malignancy, and teratogenicity). (Armstrong 2020, Jain 2021).

[0011] Biological drugs (e.g., TNF and IL inhibitors) target specific components of the immune response. However, the use of these agents is limited due to the potential development of immunogenicity, risk of serious infection and malignancy, parenteral administration, and cost. Undertreatment remains a concern, especially in severe cases and in special populations, considering the complexity of managing a multisystemic disease. (Raimondo 2017, Feldman 2016). Therefore, there is a need for new effective treatments with acceptable safety profiles and convenient routes of administration that allow for a more personalized treatment approach. (Rendon 2019, Jiang 2023).

[0012] Brilaroxazine (RP5063) is a multimodal modulator of dopamine and 5-HT receptors. Brilaroxazine exhibits high binding affinity for D2-4 and 5-HT1A receptors as a partial agonist, 5-HT2A as a weak partial agonist or neutral antagonist, 5-HT2B / 7 as an antagonist, and moderate affinity for the serotonin transporter (SERT). Petition 870250088286, dated 09 / 29 / 2025, page 46 / 77 / 24 Brilaroxazine has established efficacy, safety, and pharmacokinetic profile in phase 1 and 2 studies in healthy volunteers and patients with schizophrenia. Furthermore, preclinical studies indicate that this agent inhibits the release of multiple pro-inflammatory cytokines.

[0013] Liposomes are microparticulate or colloidal carrier systems, generally 0.025–5.0 μm in diameter. Liposomes are composed of biodegradable and biocompatible components and provide a unique opportunity to deliver drugs to cells or even within individual cellular compartments. Liposomes form spontaneously when lipids are hydrated in aqueous medium at the transition temperature. Lipids are composed of natural and / or synthetic lipids (phospholipids and sphingolipids) and may contain other bilayer constituents such as cholesterol and hydrophilic polymeric lipids. Figure 1 shows a representation of a general liposome structure.

[0014] The compositions of liposomes determine their interaction with blood and tissues. The compositions determine the net physicochemical properties of liposomes, namely, membrane fluidity, charge density, and steric hindrance permeability. They prove to be useful carriers for both hydrophilic and hydrophobic drugs. These drug delivery systems are employed for the delivery of drugs with different lipophilicities, such that a water-soluble drug will be encapsulated in the aqueous compartment; the lipophilic drug is usually bound to the lipid bilayer or dissolved in the lipid phase. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 shows a diagram of a general structure of a liposome.

[0016] Figure 2 shows the particle size (Z-mean) and particle distribution index in the liposomal dispersion by DLS measurement of brilaroxazine liposomes. Petition 870250088286, dated 09 / 29 / 2025, page 47 / 77 / 24

[0017] Figure 3 shows the HPLC chromatogram of brilaroxazine liposomes.

[0018] Figure 4 shows the HPLC chromatogram of a lipogel sample. The first peak is for brillaroxazine and the second peak is for the excipient.

[0019] Figure 5 shows the in vitro diffusion study graph of lipogel through the membrane.

[0020] Figure 6 shows the comparative effects on the Psoriasis Area and Severity Index (PASI) from Day 1 to 12 in the murine model of imiquimod-induced psoriasis. PASI, between brilaroxazine lipogel and induced psoriasis group from Day 3 to 12 (p = 0.03).

[0021] Figure 7 shows the Baker scores for sham control, psoriasis, and brilaroxazine lipogel groups in the murine model of imiquimod-induced psoriasis.

[0022] Figure 8 shows 100x magnification images of histological studies of skin using H&E staining.

[0023] Figure 9 shows images with 400x magnification of histological studies of the skin using H&E staining.

[0024] Figure 10 shows the serum level of TNF alpha in different groups of animals in the study.

[0025] Figure 11 shows the serum level of KI67 in different groups of animals in the study.

[0026] Figure 12 shows the serum level of TGF-beta in different groups of animals in the study. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention is directed to a method for treating psoriasis by administering an effective amount of brilaroxazine to an individual in need thereof. Brilaroxazine is effective in reducing one or more Petition 870250088286, dated 09 / 29 / 2025, page 48 / 77 / 24 signs or symptoms of psoriasis.

[0028] Brilaroxazine is a dopaminergic-serotonergic system stabilizer with potent partial agonist activity at dopaminergic D2, D3, and D4 receptors, and at serotonergic 5-HT1A and 5-HT2A receptors, as well as antagonist activity at serotonergic 5-HT6 and 5-HT7 receptors. Due to its potent partial agonist activity at 5-HT1A and 5-HT2A receptors, brilaroxazine reduces the production of inflammatory mediators such as TNF-α, IFN-γ, IL-1β, IL-6, and IL-8, and prevents the activation of nuclear factor-κB to induce keratinocyte activation, trigger keratinocyte deterioration, and worsen psoriasis symptoms.

[0029] Brilaroxazine (free base) is a basic, lipophilic molecule with a molecular weight of 450.36 g / mol. Its chemical structure is shown below.

[0030] Brilaroxazine is frequently found in the form of the HCl salt, with a molecular weight of 486.7 g / mol. Pharmaceutical Compositions

[0031] The present invention provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and brilaroxazine, or a pharmaceutically acceptable salt thereof. The brilaroxazine or its pharmaceutically acceptable salt in the pharmaceutical compositions is generally in an amount of about 0.01-20%, or 0.05-20%, or 0.1-20%, or 0.1-10%, or 0.1-5%, or 0.1-2%, or 0.2-15%, or 0.2-10%, or 0.2-5%, or 0.2-2%, or 1-5% (w / w) for a topical formulation; about 0.1-5% for an injectable formulation, 0.1-5% for a formulation Petition 870250088286, dated 09 / 29 / 2025, page 49 / 77 / 24 in transdermal patch, approximately 1-90% for a tablet formulation, and 1-100% for a capsule formulation.

[0032] In one embodiment, brilaroxazine is incorporated into any acceptable carrier, including creams, gels, lotions, or other types of suspensions that can stabilize the active compound and release it to the affected area by topical application. In another embodiment, the pharmaceutical composition may be in a dosage form such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injectable solutions, transdermal patches, or the like. The above pharmaceutical composition may be prepared by conventional methods.

[0033] Pharmaceutically acceptable carriers, which are inactive ingredients, may be selected by a person skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous solutions, suspensions, emulsions, microemulsions, micellar solutions, gels, and ointments. Pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline solutions and aqueous electrolyte solutions; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as hydroxide, phosphate, citrate, acetate, borate salts; and trolamine; Antioxidants such as salts, acids and / or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols and ascorbyl palmitate;Surfactants such as lecithin, phospholipids, including but not limited to phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol; poloxamers and poloxamines, polysorbates such as polysorbate 80, polysorbate 60 and polysorbate 20, polyethers such as polyethylene glycols and polypropylene glycols; polyvinyls such as polyvinyl alcohol and povidone; cellulose derivatives such as methylcellulose, hydroxypropylcellulose; Petition 870250088286, dated 09 / 29 / 2025, page 50 / 77 / 24 hydroxyethylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, die-triglycerides; acrylic acid polymers such as carboxypolymethylene gel and hydrophobically modified cross-linked acrylate copolymer; polysaccharides such as dextrans and glycosaminoglycans such as sodium hyaluronate. Other pharmaceutically acceptable carriers include xanthan gum, carrageenan, Avicel RC-591 (a combination of microcrystalline cellulose and), and polyethylene glycol. Alternatively, the active compound can be dissolved or suspended in a pharmaceutically acceptable lipid formulation, such as those described by Kalepu et al. (Acta Pharmaceutica Sinica B, 3: 361-372, 2013), for example, vegetable oil, coconut oil, castor oil, etc.

[0034] Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, which include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preservative formulation for single or multiple use.

[0035] For example, a tablet or capsule formulation of brilaroxazine may contain other excipients that are not bioactive and do not react with the active compound. The excipients of a tablet or capsule may include diluents, binders, lubricants and glidants, disintegrants, wetting agents, and release rate modifiers. Binders promote the adhesion of the formulation particles and are important for a tablet formulation.Examples of excipients in a tablet or capsule include, but are not limited to, carboxymethylcellulose, cellulose, ethylcellulose, hydroxypropylmethylcellulose, methylcellulose, Karaya gum, starch, tragacanth gum, gelatin, stearate. Petition 870250088286, dated 09 / 29 / 2025, page 51 / 77 / 24 magnesium, titanium dioxide, poly(acrylic acid) and polyvinylpyrrolidone. For example, a tablet formulation may contain inactive ingredients such as colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and / or titanium dioxide. A capsule formulation may contain inactive ingredients such as gelatin, magnesium stearate and / or titanium dioxide.

[0036] For example, a transdermal patch formulation of brilaroxazine may comprise some inactive ingredients such as 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, d-sorbitol, gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. A transdermal patch formulation may also contain a skin permeability enhancer, such as lactate esters or diethylene glycol monoethyl ether.

[0037] Topical formulations including brilaroxazin may be in the form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension. Inactive ingredients in topical formulations include, for example, but are not limited to, (emollient / permeation enhancer), diethylene glycol monoethyl ether (emollient / permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology / texture modifier), caprylic / capric triglyceride (emollient), octisalate (emollient / UV filter), silicone fluid (emollient / diluent), squalene (emollient), sunflower oil (emollient), and silicon dioxide (thickening agent).

[0038] The present application further provides a gel formulation comprising brilaroxazine liposome, a gelling and humectant agent. In one embodiment, the gel formulation comprises Petition 870250088286, dated 09 / 29 / 2025, page 52 / 77 / 24 brilaroxazine in an amount of 0.005-10%, 0.01-5% or 0.1-2% by weight. In one embodiment, the formulation has a gel-like appearance, and the bilayer lipid vesicles are intact and stable in the gel. In one embodiment, the gelling agent is carbomer 940, and the humectant is glycerin. Brilaroxazine Liposomes

[0039] In one embodiment, brilaroxazine is incorporated into bilayer lipid vesicles of a liposome composition. In another embodiment, the liposome composition comprises bilayer lipid vesicles encapsulating an aqueous solution, wherein the bilayer lipid vesicles comprise one or more phospholipids, sterol, and brilaroxazine.

[0040] The lipids used in the formation of lipid vesicles typically include lipid mixtures composed predominantly of phospholipid(s) and sterol(s). A list of phospholipids commonly used in liposome preparations can be found on page 471 of Szoka et al. (Ann Rev Biophys Bioeng (1980) 9:467). The vesicles can be formulated to include negatively or positively charged lipids, such as phosphatidic acid (PA) and phosphatidylglycerol (PG), to provide a desired surface charge on the reactant vesicles. A small amount of antioxidant, such as α-tocopherol (0.1 to 1 mol%), can be added to the lipid mixture to increase stability. A typical lipid mixture used in the formation of the brilaroxazine liposome of the present invention includes phosphatidylcholine, cholesterol, and brilaroxazine.

[0041] In one embodiment, the aqueous solution of the liposome composition comprises maltodextrin. Maltodextrin consists of D-glucose units connected in chains of varying length. The glucose units are linked primarily by α(1->4) glycosidic bonds. Maltodextrin is typically composed of a mixture of chains ranging from three to 17 glucose units in length. Liposomes of Petition 870250088286, dated 09 / 29 / 2025, page 53 / 77 / 24: Brilaroxazine encapsulating maltodextrin may provide a better drug release profile than liposomes of brilaroxazine without maltodextrin.

[0042] Brilaroxazine liposomes are prepared by first dissolving vesicle-forming lipids (e.g., brilaroxazine, phosphatidylcholine, cholesterol) in an inert organic solvent or solvent system, for example, chloroform and / or ethanol, to form an organic-phase solution of the lipids. In general, the inert organic solvent or solvent system is one in which the lipid components can be readily dissolved, at a concentration in the range of about 0.5–50 mg lipid / mL. Then the lipid solution is thoroughly dried to remove the organic solvent(s) and form a thin lipid film on the surface of a container. After drying, the thin lipid film is then hydrated with an aqueous solution. In a preferred embodiment, the aqueous solution contains maltodextrin.

[0043] In one embodiment, the brilaroxazine liposomes comprise 10-40% or 20-30% by weight of brilaroxazine.

[0044] In one embodiment, the brylaroxazin liposomes comprise 20-60% or 30-45% by weight of maltodextrin.

[0045] In one embodiment, the average particle size of brilaroxazine liposomes in a formulation is between 500-750 nm.

[0046] In one embodiment, the most intense peak of brilaroxazine liposomes in a formulation has a peak size between 900-1000 nm. Method for Treating Psoriasis

[0047] This application provides a method for treating psoriasis. The method comprises administering an effective amount of brilaroxazine to an individual in need of it. “An effective amount,” as used herein, is the amount effective for treating psoriasis by means of Petition 870250088286, dated 09 / 29 / 2025, page 54 / 77 / 24 improvement of the pathological condition or reduction of psoriasis symptoms. The method reduces one or more selected signs and symptoms from the group consisting of: red patches of skin covered with thick, silvery scales; small scaly spots; dry and cracked skin; itching, burning or sensitivity of the skin; thickened nails with depressions or ridges, and swollen and stiff joints.

[0048] The pharmaceutical composition of the present invention can be applied by local administration and by systemic administration. Local administration includes topical administration. A preferred route of administration is topical administration.

[0049] In topical administration, brilaroxazine may be contained in a topical dosage form and come into direct contact with the psoriatic plaques. Topical administration consists of applying the brilaroxazine formulation to the skin to directly treat the skin disorder or cutaneous manifestations of a disease, with the intention of restricting the pharmacological effect or the effect of brilaroxazine to the skin surface. Topical formulations are applied to minimize the flow of brilaroxazine through the skin and maximize its retention in the skin. The therapeutic effect of topical formulations depends on the ability of brilaroxazine to penetrate the skin layers, which, in turn, depends on the physicochemical properties of brilaroxazine, the carrier base, and the skin conditions. Topical formulations for the treatment of psoriasis can be administered in a wide variety of pharmaceutical forms: ointments, creams, gels, lotions, sprays, foams, etc.Through topical administration, brilaroxazine exerts its serotonergic mechanism on cells to control psoriasis. As a topical dosage form, a lower concentration is sufficient compared to the oral form to provide the required pharmacodynamic action at the application site.

[0050] Conventional semi-solid dosage forms Petition 870250088286, dated 09 / 29 / 2025, page 55 / 77 / 24. Commonly used methods present certain limitations in drug delivery due to the barrier properties of the skin. The skin is continuously involved in constructing an efficient homeostatic barrier. Liposomes are a drug delivery system that can be used for topical administration of drug molecules. Liposomes are microscopic vesicles containing amphipathic phospholipids organized in one or more concentric bilayers that enclose an equivalent number of aqueous compartments. In this form, as a spherical capsule, liposomes resemble biological membranes. Liposomes comprise biodegradable and biocompatible components and offer a unique opportunity to deliver drugs to cells or even within individual cellular compartments.Thus, semi-solid dosage forms dispersed with liposomes of brilaroxazine may offer significant advances in delivering brilaroxazine to the deeper layers of the skin in severe psoriatic conditions.

[0051] Systemic administration includes oral, parenteral (such as intravenous, intramuscular, subcutaneous, or rectal), and other systemic routes of administration. In systemic administration, the active compound first reaches the plasma and then distributes to the target tissues.

[0052] In one embodiment, the composition is applied topically to the affected area and rubbed into the skin. The composition is applied topically at least once or twice daily, or three to four times daily, depending on the medical condition and the pathology of the disease, whether chronic or acute. In general, the topical composition comprises about 0.01-10% (w / w) of the active compound brilaroxazine. For example, the topical composition comprises about 0.1 to 2% (w / w) of the active compound. Depending on the size of the affected area, 0.2-85 mL, typically 0.2-10 mL, of the topical composition is applied to the individual per dose. The active compound penetrates the skin and is released at the site of discomfort. Petition 870250088286, dated 09 / 29 / 2025, page 56 / 77 / 24

[0053] A person skilled in the art will recognize that a wide variety of release mechanisms are also suitable for the present invention.

[0054] The present composition of brilaroxazine liposomes is useful in the treatment of mammalian subjects, such as humans, horses and dogs. The present invention is particularly useful in the treatment of humans.

[0055] The following examples further illustrate the present invention. These examples are merely illustrative of the present invention and should not be interpreted as limiting. EXAMPLES Example 1. Preparation of Brilaroxazine Liposomes

[0056] Table 1 shows the composition of the brilaroxazine liposome formulation. Table 1. No. List of Ingredients Percentage CAS No. 1. Briloxazin 24.53 1239729-06-6 2. Lecithin 34.76 8002-43-5 3. Cholesterol 2.97 57-88-5 4. Maltodextrin 37.74 9050-36-6 5. Purified water (for hydration of the lipid film) Qs NA Solvents used for the preparation of the dry lipid film 6. Chloroform (which was dried in the process) NA 67-66-3 7. Ethanol (which was dried in the process) NA 64-17-5

[0057] Brilaroxazine liposomes were prepared by the lipid hydration method. Briefly, phosphatidylcholine and cholesterol were dissolved in a suitable solvent (chloroform and / or ethanol) and brilaroxazine was dissolved in the same solvent. The drug-lipid solution was then dried at 45-50°C in a rotary evaporator, using vacuum to completely remove the solvent. After all solvent removal, a thin film formed in the round-bottom flask. The round-bottom flask containing the lipid film was kept under vacuum for 12-24 h to completely remove any traces of solvents present in the thin lipid film. After 12-24 h of drying, the thin film was hydrated with 66 mL of maltodextrin solution at 60°C (concentration of 39.57 mg / mL). Petition 870250088286, dated 09 / 29 / 2025, page 57 / 77 / 24 Example 2. Particle Size Analysis and Zeta Potential of Brilaroxazine Liposomes

[0058] Liposomes prepared from Example 1 were observed at different magnifications using an optical microscope for confirmation during the hydration process. Observation under an optical microscope at different magnifications (10x, 20x, and 40x) to confirm the prepared spherical liposomal vesicles occurred throughout the hydration process.

[0059] Liposomes were analyzed for particle size using the DLS (dynamic light scattering) method for particle size and drug content analysis. The Z-mean (particle size) was measured for the prepared liposomes. Figure 2 shows the particle size (Z-mean) and particle distribution index in the liposomal dispersion by DLS measurement of brilaroxazine liposomes.

[0060] Zeta potentials were estimated from the experimentally determined electrophoretic mobility of the particles. The value of the zeta potential indicates the stability of the colloidal dispersion.

[0061] Zeta potential value (mV): • 0 to 5 - Rapid coagulation or flocculation • 10 to 30 - Incipient instability • 30 to 40 - Moderate stability • 40 to 60 - Good stability • > 61 - Excellent stability

[0062] In general, colloidal dispersions with zeta potential values ​​greater than +30 mV or less than -30 mV exhibit a high degree of stability. The higher the zeta potential value (both positive and negative), the better the stability.

[0063] Table 2 shows the particle size and zeta potential analysis of liposomes by the DLS method. Petition 870250088286, dated 09 / 29 / 2025, page 58 / 77 / 24 Table 2. Liposomes No. Particle Size (Z-Average) nm Zeta Potential (mV) Liposomes RP5063 630.9 38.8 Example 3. Measurement of Drug Content by HPLC

[0064] The drug content in liposomes was analyzed by the HPLC method. HPLC System

[0065] Shimadzu HPLC system (LC-2030C Plus, Serial No.: L21445711704 AE, Made in Japan), autosampler, UV detector, data acquisition system. An equivalent system may be used as a substitute. HPLC column

[0066] Shimadzu Shim-Pack GIST C18, 5 pm, 250 x 4.6 mm or equivalent column. Reagent preparation Mobile phase A

[0067] · Dissolve 2.72 g of KH2PO4 in 1000 mL of ultrapure water (0.02M solution).

[0068] · Adjust the pH to 3.0 with phosphoric acid.

[0069] · Mix 90 parts of the above buffer with 10 parts of acetonitrile.

[0070] · Filter through membrane before use. Mobile phase B

[0071] · Mix 90 parts acetonitrile with 10 parts ultrapure water. Adjust the pH to 3.0 with phosphoric acid.

[0072] · Filter through membrane before use. Diluent

[0073] · Prepare a mixture of acetonitrile and phosphate buffer (section 6.2.1.1) (85:15) for drug content / encapsulation efficiency. Sample preparation for drug content and incorporation efficiency. Petition 870250088286, dated 09 / 29 / 2025, page 59 / 77 / 24 Drug content

[0074] Place the required amount of liposome sample (complete dispersion) in a volumetric flask, add the required volume of diluent (6.2.3) and mix well. Keep this mixture in an ultrasonic bath for 30-45 minutes at 60°C. Remove the required volume of the prepared sample and dilute to the required concentration. The assay concentration / drug content is 20 pg / mL. Incorporation efficiency

[0075] Place the required amount of liposome sample in a centrifuge tube and centrifuge the liposome dispersion at 10,000 rpm for 30 minutes at 20°C. Remove the supernatant solution and collect the pellet. Add the required volume of diluent to the liposomal pellet and mix well. Keep this mixture in an ultrasonic bath for 30-45 minutes at 60°C. Withdraw the required volume of the prepared sample and dilute to a drug concentration of 20 pg / mL. Standard solution

[0076] Prepare a 20 pg / mL standard solution with the diluent above. Analysis

[0077] Configure HPLC using the following parameters: Column: Shimadzu Shim-Pack GIST C18, 5 pm, 250 x 4.6 mm or equivalent Flow rate: 1 mL / min Injection volume: 20 pL Detection: UV @215 nm Column temperature: 30°C Run time: 5-7 minutes HPLC conditions: mobile phase A, 25%; mobile phase B, 75% Identification

[0078] Compare the drug peak retention time Petition 870250088286, dated 09 / 29 / 2025, page 60 / 77 / 24 standard / pure and peak of the drug sample Result

[0079] The HPLC chromatogram is shown in Figure 3. The HPLC results show that the drug content is 96% and the drug incorporation efficiency into the liposome is 73%.

[0080] The final composition of the formulation was consistent with bryoxazin (24.53%), lecithin (34.75%), cholesterol (2.97%), maltodextrin (37.74%) and purified water for hydration of the lipid film. Example 4. Preparation of Liposomal Gel Formulations

[0081] The liposomal gel was prepared by incorporating a liposome dispersion into a gel formulation. First, the base gel was prepared, and then the liposome dispersion was added and thoroughly mixed to result in the liposomal gel or lipogel. Various percentages of lipogel formulation (0.25% to 1.5% brilaroxazin) were prepared as needed. Table 3 shows the composition of the lipogel formulation. Table 3. Function of ingredients Lipogel Formulation - RPLG Percentage (%) Gelling agent Carbomer 940 0.65 - 0.85 Humectant Glycerin 5.00 pH modifier Triethanolamine 0.10-0.25 Preservative Phenoxyethanol 1.00 Vehicle Purified water Qs Brilaroxazine Liposomal dispersion RP5063 Equivalent to 0.25% or 1.5% brilaroxazine

[0082] The prepared liposomal gel formulation was evaluated for physical appearance and pH. All gel formulations were observed under an optical microscope to verify intact liposomes in the gel formulation. The liposomal gel formulation presented a white cream gel appearance, with a pH of 5-6, and microscopic examination showed the presence of liposomes. Furthermore, the liposomal particles were intact and stable in all gel formulations. Example 5. Lipogel Analysis by HPLC

[0083] The lipogel sample was placed in a volumetric flask, Petition 870250088286, dated 09 / 29 / 2025, page 61 / 77 / 24 added diluent and well mixed. The brilaroxazine content was analyzed by HPLC according to the same protocols as Example 3.

[0084] Comparing the retention time of the pure drug peak and the sample peak, the drug content was calculated to be 95.12%.

[0085] The HPLC chromatogram of a lipogel sample is shown in Figure 4. The first peak is for brilaroxazine and the second peak is for the excipient. The brilaroxazine peak is sharp and separate from the excipient peak. Example 6. In vitro diffusion / permeation studies of Lipogel

[0086] The prepared lipogels were analyzed for drug diffusion / permeation using a Franz diffusion cell. The Franz diffusion cell was filled with PBS buffer pH 7.4. A regenerated cellulose dialysis membrane, surface-treated and neutralized with PBS pH 7.4 (molar mass cutoff point: 12000 to 14000), was placed in the receiving compartment, and a weighed amount of lipogel was placed in the donor compartment. The receiving solution was stirred with a magnetic stirrer, and skin temperature was maintained in the diffusion cell by circulating thermostated water in the outer jacket. At different time intervals, samples were withdrawn through a sampling port and replaced with the same volume of plain PBS. The withdrawn sample was mixed with an equal volume of diluent for HPLC and analyzed for drug content at different time intervals.The percentage of drug diffusion, flow rate, and permeation coefficient were calculated for each lipogel formulation. Time versus percentage of drug diffusion / release was plotted using GraphPad Prism software Version 6.01. HPLC analysis of drug diffusion samples

[0087] The HPLC analysis method, system and columns were the same as described in Example 3, except that a mixture of acetonitrile and Petition 870250088286, dated 09 / 29 / 2025, page 62 / 77 / 24 phosphate buffer (60:40) was used for the drug diffusion / permeation studies. Sample preparation for diffusion / permeation analysis

[0088] Mix an equal volume of diluent with the diffusion / permeation sample fluid taken from the Franz diffusion apparatus. Mix well in a vortex mixer and filter the solution through a syringe filter. Results

[0089] The HPLC chromatogram results of the lipogel diffusion sample show a sharp and separate brilaroxazine peak.

[0090] Figure 5 shows the in vitro diffusion study graph of the lipogel through the membrane. The release profile showed constant and sustained release of brilaroxazine from the formulation throughout the 8-hour study period.

[0091] Table 4 shows the results of the in vitro diffusion study of the lipogel formulations. Table 4. Formulation Flow (µg / cm² / h) Permeation Coefficient (cm / h) R² Value Lipogel formulation with maltodextrin 12.02 3.28 0.9984 Lipogel formulation without maltodextrin 5.48 1.92 0.9633

[0092] The lipogel formulation containing liposomes with maltodextrin showed a better drug release profile and higher flux and permeation values ​​in the in vitro diffusion study than liposomes without maltodextrin. This may be due to the increased solubility of RP5063 in the liposomal gel and the optimal particle size distribution in the formulation. Example 7. Preclinical in vivo studies - Psoriasis Model

[0093] BALB / c mice (n=6 / group) were used in this experiment, and the animals were maintained according to a protocol approved by the Institutional Animal Use Ethics Committee. Imiquimod cream (5%) was used as an inducing agent for psoriasis pathology. Psoriasis was Petition 870250088286, dated 09 / 29 / 2025, pp. 63 / 77 / 24 induced by applying imiquimod to the shaved back skin of the animals in the morning for 12 days. The lipogel formulation under test was applied to the animals at night for 12 days. Imiquimod was applied until the last day of the experiment. All animals were observed for the following parameters: PASI score, Baker score, histology by H&E staining, and serum cytokine analysis (TNF-alpha, KI67, TGF-beta). Table 5 shows the animal groups used in the preclinical studies. Table 5. Group Formulations used Number of mice Days of treatment Group 1 Normal control group 6 - Group 2 Psoriasis control group 6 1-12 Group 3 Psoriasis + Lipogel formulation group 6 1-12 PASI Score

[0094] The animals were observed daily for signs of imiquimod-induced psoriasis toxicity, and the PASI score was calculated for each group. Figure 6 illustrates the composite PASI score for Days 1-12. The induced group (Psoriasis Group) showed higher PASI scores than the non-induced control group (Sham Control Group) (p = 0.001). The magnitude differences increased between these two groups from Day 3 to Day 11. The Brilaroxazine Lipogel group showed an increase in PASI scores from Day 3, peaking on Days 7 and 8, and declining to a plateau level on Days 10-12. The scores were higher in magnitude than those of the Sham Control Group, but did not reach the same level as the Psoriasis Group. The PASI scores for the Brilaroxazine Lipogel group were consistently lower than those of the Psoriasis-Induced Group from Day 3 to 12 (p=0.03). The maximum difference in magnitude appeared on Days 11 and 12. Backer Score

[0095] At the end of the 12th day of the study period, the animals were sacrificed, the skin was collected, and histology was performed. Signs of psoriasis toxicity were checked on the skin of each animal, and the score of Petition 870250088286, dated 09 / 29 / 2025, pp. 64 / 77 / 24 Baker's score was calculated for each group. Baker's score showed a significant reduction in animals treated with the lipogel formulation. Figure 7 shows that the topical brilaroxazine formulation significantly treated (P=0.003) animals with psoriasis. Histology (H&E Staining)

[0096] Figure 8 shows 100x magnification images of histological studies of the skin. Table 6 describes the observations of the histological skin samples at 100x magnification. Table 6. Group Observations (100x) Simulated control group Normal epidermis (1-3 layers), without inflammatory infiltration Psoriasis control group Increased epithelial layers (3-7 layers, green), increased keratinization, Munro abscess (red arrow), severe inflammatory infiltration (blue) Psoriasis + Brilaroxazine Lipogel: reduced epithelial thickness (3-4 layers), reduced inflammatory infiltration, absence of parakeratinization, absence of Munro abscess

[0097] Figure 9 shows images at 400x magnification of histological studies of the skin. Table 7 shows observations of histological skin samples at 400x magnification. Table 7. Group Observations (400x) Simulated control group 1-3 layer epithelium, no inflammatory infiltration, very little keratin in the stratum corneum Psoriasis control group Severe acute and chronic inflammatory infiltration, Kogoj pustule Psoriasis + Brilaroxazine Lipogel Reduced epithelial thickness, reduced inflammatory infiltration

[0098] In summary, histological evaluation included direct observation at 100x and 400x magnification. Tables 6 and 7 and Figures 8 and 9 provide histological observations and H&E staining at both magnifications. Differences appeared between the Sham Control group and the Psoriasis-Induced and Brilaroxazine Lipogel groups, as well as between the latter two. Comparisons of the Baker score (Figure 7) reflected significant effects for the sham control group (p=0.001) and the brilaroxazine lipogel group (p=0.003), compared to the psoriasis cohort. This observation highlights the therapeutic effect of Brilaroxazine Lipogel. Serum cytokine levels Petition 870250088286, dated 09 / 29 / 2025, pages 65 / 77 / 24

[0099] At the end of the 12-day study period, the animals were sacrificed, blood was collected, and serum was separated. The serum cytokines TNF-alpha, KI67, and TGF-beta were analyzed by the ELISA method.

[00100] Figure 10 shows the serum TNF-alpha level in different groups of animals in the study. Test results show that the brilaroxazine formulation reduced the serum TNF-alpha level in animals with induced psoriasis, and the TNF-alpha level was comparable to that of animals in the sham control group.

[00101] Figure 11 shows the serum KI67 level in different groups of animals in the study. Test results show that the brilaroxazine formulation significantly reduced (P = 0.001) the serum KI67 level in animals with induced psoriasis, and the serum KI67 level was comparable to that of animals in the sham control group.

[00102] Figure 12 shows the serum TGF-beta level in different animal groups in the study. Test results show that the lipogel formulation significantly reduced (P = 0.008) the serum TGF-beta level in animals with induced psoriasis compared to animals in the psoriasis control group.

[00103] It should be understood that the above describes preferred embodiments of the present invention and that modifications may be made without departing from the scope of the present invention as set forth in the claims. Petition 870250088286, dated 09 / 29 / 2025, pp. 66 / 77

Claims

CLAIMS 1. Use of an effective amount of brilaroxazine, or a pharmaceutically acceptable salt thereof, characterized in that it is in the preparation of a medicament for treating psoriasis in an individual who needs it.

2. Use according to claim 1, characterized in that brilaroxazine is administered topically to the individual.

3. Use according to claim 2, characterized in that brilaroxazine is incorporated into liposome bilayer lipid vesicles.

4. Use according to claim 3, characterized in that the liposomes comprise one or more phospholipids, sterol and brilloxazin or a pharmaceutically acceptable salt thereof, and encapsulate an aqueous solution comprising maltodextrin.

5. Use according to claim 4, characterized in that the liposomes comprise 20-30% by weight of brilaroxazine.

6. Use according to claim 4, characterized in that the liposomes are contained in a gel formulation.

7. Use according to claim 4, characterized in that the gel formulation comprises 0.1-2% of brilaroxazin.

8. Use according to claim 1, characterized in that brilaroxazine is administered systemically to the individual.

9. Use according to claim 1, characterized in that the method reduces one or more selected signs and symptoms from the group consisting of: red patches of skin covered with thick, silvery scales; small scaly spots; dry and cracked skin; itching, burning or sensitivity of the skin; thickened nails with depressions or ridges; and swollen and stiff joints. Petition 870250088286, dated 09 / 29 / 2025, pp. 67 / 77

Images